Harnessing oral mucosa vaccination to drive protective HIV antibody responses

利用口腔粘膜疫苗接种来驱动保护性艾滋病毒抗体反应

• 批准号: 9296134
• 负责人: D. Noah Sather
• 金额: $ 85.59万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296134
• 关键词: AIDS/HIV problem; ALVAC; Adjuvant; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Automobile Driving; Biological Assay; Biological Markers; Birds; Cells; Cheek structure; Dose; Environment; Epitopes; Exhibits; Formulation; Generations; Goals; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunization; Immunologist; Infectious Diseases Research; Injection of therapeutic agent; Innate Immune Response; Intramuscular; Laboratories; Lymphoid; Macaca; Membrane; Memory B-Lymphocyte; Methodology; Molecular Conformation; Mucous Membrane; Multiparametric Analysis; Oral; Oral cavity; Oral mucous membrane structure; Organ; Pathway interactions; Peripheral; Poxviridae; Recombinants; Regimen; Route; SIV; Surface; TLR4 gene; TLR7 gene; Testing; Tissues; Training; Vaccinated; Vaccination; Vaccines; adaptive immune response; density; design; env Gene Products; exhaustion; experimental study; global health; improved; intraepithelial; mucosal site; mucosal vaccination; neutralizing antibody; next generation; pandemic disease; prevent; response; transmission process; vaccination strategy; vaccine candidate; vaccine development; vaccine response; vaccine trial

Developing an effective vaccine against HIV/AIDS remains an important global health target to inhibit and reverse the high level of HIV-1 transmission currently ongoing around the world. To date, there have been four large HIV-1 vaccine trials, of these only RV144 exhibited a limited, but significant protection (31.2%) from HIV- 1 acquisition. The assessment of the results from this study has revealed a number of key correlates of protection, including antibodies that target a conformational epitope in the V1V2 region of Env. It is clear that new vaccination methodologies are needed to improve upon the findings in the RV144 trial by generating high titers of V1-V2 and functional antibodies, creating long lived B cell memory, and driving antibody maturation toward broadly neutralizing activity. The oral mucosal tissues provide a unique environment in which to vaccinate, owing to its accessible lymphoid organs, high density of immune cells and increased potential for generating a mucosal response that is able to prevent HIV-1 acquisition at a mucosal surface. We propose a vaccination strategy to deliver recombinant HIV-1 trimeric Envelope (Env) protein vaccines directly to the oral mucosa (buccal mucosa of the cheek) by intra-epithelial (IEp) vaccination. Vaccines will be tested with two adjuvant formulations designed to stimulate strong innate induction through TLR4 and TLR7/8 pathways. The goal of this proposal is to optimize oral mucosal vaccination of the HIV-1 Env protein in order to enhance Env- specific antibody responses, and to characterize the effect of oral vaccination with Env by conducting a thorough multi-parametric assessment of vaccine-elicited immunity. The first Specific Aim will assess the innate immune response to the vaccine, with a focus on the influence of the vaccine at the buccal mucosa where the vaccine is administered by IEp injection. Innate immune changes are interesting for their potential to reveal a biomolecular signature that we believe will correspond to superior HIV-1 ENV antibody responses. The second and third Specific Aims will evaluate whether supplying Env to the oral mucosa drives superior antibody responses at mucosal sites and systemically. An assessment of the neutralization and ADCVI activity will provide a functional assessment that can be correlated with the findings from studies of the innate immune response. Aims 2 and 3 will also involve a mechanistic assessment of the anti-Env antibody response through an assessment of both CD4 T Follicular Helper cell responses and antibody maturation in these macaques. In addition to the optimization of oral mucosal IEp vaccination and the exhaustive multi-parametric analyses, the combined expertise of the Sodora and Sather laboratories is one of the major strengths of this application. The experiments outlined in this proposal utilize an oral mucosal IEp delivery of next-generation HIV-1 Env antigens, as well as an assessment of both innate and adaptive immune responses. This comprehensive approach results in a high degree of confidence that undertaking these studies will make a significant contribution to HIV-1 vaccine development and advance efforts toward reversing the ongoing HIV-1 pandemic.

开发有效的艾滋病毒/艾滋病疫苗仍然是一个重要的全球卫生目标， 扭转目前世界各地HIV-1传播的高水平。到目前为止，已经有四个 大型HIV-1疫苗试验中，只有RV 144表现出有限的，但显着的保护作用（31.2%）， 1收购。对这项研究结果的评估揭示了一些关键的相关因素， 保护，包括靶向Env的V1 V2区中的构象表位的抗体。很明显 需要新的疫苗接种方法来改善RV 144试验的结果， V1-V2和功能性抗体的滴度，产生长寿的B细胞记忆，并驱动抗体成熟 进行广泛的中和反应口腔粘膜组织提供了一个独特的环境， 接种疫苗，由于其可接近的淋巴器官，高密度的免疫细胞和增加的潜力， 产生能够防止HIV-1在粘膜表面获得的粘膜应答。我们提出了一个 将重组HIV-1三聚体包膜（Env）蛋白疫苗直接递送至口服的疫苗接种策略 通过上皮内（IEp）接种，在口腔粘膜（颊粘膜）上接种。疫苗将用两种 佐剂制剂设计为通过TLR 4和TLR 7/8途径刺激强先天诱导。的 该建议的目的是优化HIV-1 Env蛋白的口腔粘膜接种，以增强Env-1的免疫原性。 特异性抗体应答，并通过进行 对疫苗引发的免疫力进行全面的多参数评估。第一个具体目标将评估 对疫苗的天然免疫应答，重点是疫苗对颊粘膜的影响 其中通过IEp注射施用疫苗。先天性免疫变化是有趣的，因为它们有可能 揭示了一个生物分子特征，我们相信这将对应于上级HIV-1 ENV抗体应答。 第二个和第三个具体目标将评估向口腔粘膜提供Env是否会带来上级 粘膜部位和全身的抗体应答。中和和ADCVI活性评估 将提供一个功能评估，可以与先天免疫研究的结果相关联， 反应目的2和3还将涉及抗Env抗体应答的机制评估， 在这些猕猴中评估CD 4 T滤泡辅助细胞应答和抗体成熟。在 除了优化口腔粘膜IEp疫苗接种和详尽的多参数分析外， Sodora和Sather实验室的综合专业知识是该应用的主要优势之一。的 该提案中概述的实验利用下一代HIV-1 Env的口腔粘膜IEp递送， 抗原，以及先天性和适应性免疫应答的评估。这一全面 这种方法导致高度的信心，进行这些研究将使一个显着的 为HIV-1疫苗的开发做出贡献，并推动扭转目前HIV-1流行的努力。